Hemophilia is an X-linked bleeding disorder that results from a deficiency in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Patients are conventionally treated by protein replacement therapies using plasma-derived or recombinant factor VIII or factor IX. Gene therapies for both hemophilia A and B are in various stages of pre-clinical and clinical trails. However, 25% of hemophilia A patients develop inhibitors (e.g., antibodies) to factor VIII and about 5% of hemophilia B patients generate inhibitors to factor IX. These inhibitors lead to the ineffectiveness of protein replacement or gene replacement therapies.
It is known that basal levels of Factor VIIa in plasma are greatly reduced in patients with hemophilia B (Factor IX deficiency) and, to a lesser extent, patients with hemophilia A (Factor VIII deficiency). Wildgoose et al., Blood 1:25-28 (1992). In the absence of activated FVIIa, the intrinsic blood clotting pathway involving FVII and FIX, is severely limited in effective coagulation. Recently, recombinant activated Factor VII (rFVIIa, NovoSeven, Novo, Nordisk) has been shown to have therapeutic value to bypass or correct the coagulation defects in hemophilia A and B patients with inhibitors, especially in patients with inhibitors who were undergoing surgical procedures. However, recombinant FVIIa is expensive to manufacture. Anther critical problem is the short half life (2 hours) of recombinant FVIIa. Therefore, recombinant FVIIa therapy requires an intravenous infusion of high doses of the protein every 2 hours.
A need exists for alternative therapies for blood coagulation disorders such as hemophilia.